Pulmonary vascular balance in congenital diaphragmatic hernia: enhanced endothelin-1 gene expression as a possible cause of pulmonary vasoconstriction.
BACKGROUND
Pulmonary hypoplasia and persistent pulmonary hypertension (PPH) are the principal causes of the ongoing mortality in congenital diaphragmatic hernia (CDH) presenting with respiratory insufficiency within 6 hours after birth. Endothelin-1 (ET-1) is an endothelial-derived vasoconstrictor, which could play an important role in modulating pulmonary vascular tone in PPH. ET-1 exerts its role in controlling vascular tone through two different subtype receptors, endothelin-A receptor (ETA) which is responsible for vasoconstriction and endothelin-B receptor (ETB) which is responsible for vasodilatation by induction of nitric oxide synthase.


METHODS
We examined the pulmonary expression of ET-1, ETA and ETB mRNAs in a rat model of CDH. CDH was induced in rats by administration of 100 mg of nitrofen dissolved in olive oil on day 10 of gestation. Fetal lungs were collected after cesarean section on gestational day 22 (term) and processed for Northern blot analysis and quantitative polymerase chain reaction (PCR).


RESULTS
Significantly (P<.05) enhanced levels of ET-1 mRNA were observed in CDH rats compared with control rats. In contrast to equal levels of ETB mRNA, a two- to fourfold increase in ETA mRNA levels were observed in CDH as compared with control rats.


CONCLUSIONS
The upregulated expression of ET-1 and ETA receptor mRNA before birth strongly support the reason for pulmonary vasoconstriction and altered pulmonary vascular muscularization in CDH. Consequently in the clinical setting, the use of endothelin receptor blockade for the treatment of PPH may be considered against the background of the unpredictable and variable response to inhaled nitric oxide in newborns with CDH.
Okazaki
T
T
Department of Pediatric Surgery, Sophia Children's Hospital, Rotterdam, The Netherlands.
Sharma
H S
HS
McCune
S K
SK
Tibboel
D
D
D000818:Animals; D015152:Blotting, Northern; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000503:physiopathology; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000196:embryology; D010547:Persistent Fetal Circulation Syndrome / Q000209:etiology*; D010647:Phenyl Ethers; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D014661:Vasoconstriction / Q000502:physiology
D019332:Endothelin-1; D010647:Phenyl Ethers; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C007350:nitrofen